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(The FASEB Journal. 1998;12:1473-1480.)
© 1998 FASEB

RESEARCH COMMUNICATION

Selective deficit in antibodies specific for the superantigen binding site of gp120 in HIV infection

Laure Juompana, Patrick Lambinb, and Moncef Zoualia,1

a Département d'Immunologie, Institut Pasteur, 75015 Paris, France
b Unité d'Immunologie Transfusionelle, INTS, 75015 Paris, France


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
HIV infection is characterized by accelerated apoptosis and progressive loss of B cells. To see whether these abnormalities are related to the property of gp120 to act as a superantigen for VH3+ B cells, we probed the temporal development of VH3+ antibodies in HIV-1-infected subjects over a 7-year period. We found that VH3+ antibodies specific for the gp120 superantigen binding site are deficient. Since VH3+ antibodies impart protective responses to infectious agents, we quantified VH3+ antibodies in serum samples from HIV-seropositive slow progressors and from patients who progressed to AIDS-related manifestations. We found that paucity in VH3+ antibodies is a marker of rapid clinical decline. Remarkably, anti-gp160 VH3+ antibodies showed a gradual decrease in progressors and, with time, varied depending on the viral load. We conclude that disease aggravation is associated with a decrease of the magnitude of the humoral response, that VH3+ antibodies play an important role in protection, and that their underexpression may accelerate disease progression. We propose that vaccine preparations able to trigger VH3+ antibodies might confer a better protection against HIV infection. This work also represents a novel mechanism of humoral deficiency resulting from the capacity of a viral antigen to affect an important subset of the B cell repertoire and to induce B cell death by apoptosis.—Juompan, L., Lambin, P., Zouali, M. Selective deficit in antibodies specific for the superantigen binding site of gp120 in HIV infection. FASEB J. 12, 1473–1480 (1998)


Key Words: B cell death • immunoglobulin isotypes • disease progression


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
HIV-INFECTED SUBJECTS exhibit a profound disturbance in the B cell compartment, including hypergammaglobulinemia, circulating activated B lymphocytes, spontaneous in vitro immunoglobulin (Ig)2 secretion, and serum autoantibodies. This hyperactivity of B lymphocytes contrasts with a decrease in their ability to respond to various mitogens and recall antigens in vivo and in vitro (1–5). Since there is no evidence that HIV can infect B cells, several indirect mechanisms have been proposed to account for these B cell abnormalities, including abnormal cytokine production by HIV-infected inflammatory cells (6), progressive T cell decline (7), expansion of HIV-specific B cell precursors (8), and hyperactivation of B cells (9, 10).

Insight into the origin of the severe impairment of the functional humoral response in HIV infection came from studies of the B cell repertoire showing a marked underexpression of the VH3+ gene family (11–13). This VH3 gene family underexpression is likely related to the capacity of gp120 to act as a superantigen (SAg) for VH3+ B cells (14). Since, in normal conditions, members of this family dominate the antibody repertoire and impart protective humoral responses to infectious agents (15, 16), the marked deficit of VH3+ anti-HIV antibodies may contribute to disease aggravation seen in rapid progressors (RP).

Recently, the gp120 motifs responsible for gp120 SAg property were identified (17, 18). Here, we address directly the question of whether the deficiency of VH3+ antibodies in HIV-infected subjects is due to gp120 SAg activity by probing the VH3+ antibody response directed to the gp120 SAg binding site. To see whether changes in the antibody repertoire to HIV-1 antigens may influence disease progression, we have also examined the temporal development of VH3+ antibodies in a group of RPs and compared it to that of slow progressors (SPs) throughout the course of infection.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
We studied two groups of subjects. The first group, classified as SPs, was defined as having a median duration of infection of more than 6 years, stable CD4+ counts, and no AIDS-related symptoms. None of these individuals had been treated with antiretroviral agents. This group was contrasted with a matched group of RPs, defined as patients with a variable duration of HIV-1 infection (mean=4.2 years), a decline in CD4+ cell counts, and the occurrence of an AIDS-defining condition. All RPs were receiving antiviral therapy. The disease stage and the CD4+ cell counts of these patients are shown in Table 1. Serial serum samples were collected approximately every 6 months from each subject throughout the course of infection over a 7-year period. Ten HIV-1-seronegative subjects were used as controls.


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  		Table 1. Clinical and laboratory characteristics of the subjects studied

Human monoclonal antibodies and recombinant protein
Human monoclonal antibodies (mAb's) NG3B7 and C31 (ref 19) were a gift of Drs. D. Goossens (INTS, Paris) and C. Desgranges (INSERM, Lyon, France), respectively. mAb's F105D (ref 20) and 257-D (ref 21) were from the AIDS National Institute of Allergy and Infectious Diseases, Research and Reference Reagent Program, Division of AIDS, National Institutes of Health from MicrogeneSys (West Haven, Conn.). Antibody T48.16-G8 has been previously described (19). Recombinant gp160MN/LAI was provided by Dr. M.-P. Kieny (Transgène, Strasbourg, France).

Synthetic peptides
A peptide corresponding to the third variable region (V3) of gp120 HIVLAI (AA positions: 301–333) was obtained from the `Agence Nationale de Recherche sur le SIDA' (Paris). Two peptides corresponding to the fourth variable region (V4; AA positions: 392–414) and the fourth constant region (C4; AA positions: 414–434) of gp120 HIVMN were from the AIDS National Institute of Allergy and Infectious Diseases, Research and Reference Reagent Program, Division of AIDS, National Institutes of Health from MicrogeneSys. All peptides were soluble at neutral pH.

Quantification of immunoglobulin isotypes
The concentration of total Ig's in the serum of HIV-infected subjects was determined by an enzyme-linked immunoassay (ELISA) assay in which microtiter wells (Nunc, Roskilde, Denmark) were coated overnight at 4°C with 500 ng/well of goat anti-human IgM or IgG and rabbit anti-human IgA (Sigma, St. Louis, Mo.) in borate-buffered saline (pH 8.4). For each Ig isotype, a standard calibration curve was obtained using purified human IgM (Sigma), IgG, or IgA (Chemicon International, Temecula, Calif.).

Anti-gp160 and anti-peptide antibody titers
ELISA assays for antibodies to gp160 and V3, C4, and V4 epitopes were performed on microplates coated with gp160 and V3, C4, and V4 synthetic peptides (100 ng/well). After three washings with phosphate-buffered saline containing 0.1% Tween-20 and saturation with 1% bovine serum albumin (ICN, Bryan, Ohio) for 2 h at 37°C, dilutions of human sera were added for 90 min at 37°C. After washings, 100 µl of a mixture of alkaline phosphatase-conjugated goat anti-human IgM, IgG, or IgA (Sigma) was added for 1 h at 37°C and bound antibodies were visualized using the para-nitrophenol phosphate alkaline phosphatase substrate (Sigma). Optical density was recorded at 450 nm. For each sample, nonspecific binding observed with normal human serum was subtracted from the value obtained with the serum from HIV-infected subjects, and midpoint titers were defined as the serum dilution giving half-maximal binding after background subtraction.

Measurement of VH3+ immunoglobulins
Protein A from Staphylococcus aureus (SpA) expresses binding sites for both VH3+ Ig's and the constant region domain of IgG. Iodine monochloride modification of SpA selectively inactivates IgG binding activity of protein A without affecting its Ig-SpA binding activity (22). We first treated SpA (Sigma) with iodine chloride to inactivate its Fc binding site (Tyr-SpA). The iodinated protein was then biotinylated and the resulting Tyr-SpA-biotine conjugate was used as a probe to quantify VH3+ Ig's in an ELISA assay. Microtiter wells were coated with anti-IgM, IgG, or IgA antibodies. After serum incubation and washings, wells were stained with Tyr-SpA-biotine for 90 min at 37°C. After washings, an alkaline phosphatase-labeled Extravidine conjugate (Sigma) 1/70,000 diluted was added. After 1 h incubation at 37°C, binding was revealed as described above. For each Ig isotype, a standard curve was obtained using a VH3+ human monoclonal Ig.

Quantification of HIV-specific VH3+ antibodies
Microtiter wells were coated with 100 ng of rgp160 or synthetic peptides (corresponding to V3, V4, and C4 domains of gp120) and the ELISA was continued as described for detection of VH3+ Ig's. Nonspecific binding observed with normal human serum was subtracted from the values obtained with sera from HIV-infected subjects. The proportions of VH3+ antibodies specific for each ligand (rgp160 and V3, V4, and C4 synthetic peptides) were expressed as the percentage of the total serum antibody repertoire of the corresponding specificities. This assay system used to measure VH3+ antibodies requires that the capture antigen and SpA reagent should bind to different sites on the test antibodies. In a series of experiments, we found that gp160 and SpA do not compete for the same binding site on VH3+ immunoglobulins (22b), making it unlikely that competition between the capture reagent and the probing reagent could confound the interpretation of antibody levels.

HIV-1 viral load
Quantitation of HIV-1 viral RNA was performed in the patient's serum samples by a nucleic acid sequence-based amplification method (23) using a kit from Organon Teknika (Boxtel, The Netherlands).

Statistical analysis
We applied the Student's t test or the Student-Newman-Keuls test when analyzing the results. P values <0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
To analyze the humoral response of HIV-infected subjects, we first determined the concentration of total IgM, IgG, and IgA in 98 serum samples from SP and RP subjects. Whereas IgM levels were within normal ranges, the concentration of IgG was increased in both SPs and RPs compared with controls, but no significant difference was observed between SPs and RPs ( Table 2). Compared with controls, IgA levels were increased in RPs but decreased in SPs. Thus, progressors were generally hypergammaglobulinemic, a finding consistent with reports that HIV infection is often, but not invariably, associated with elevations in serum Ig's (24–26).


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  		Table 2. Serum IgM, IgG, and IgA concentrations in SPs and RPs2tfa

Since VH3+ Ig's represent normally about half of serum Ig's and impart protective humoral responses to infectious agents (15, 16), we designed a test to quantify the representation of VH3+ antibodies in HIV infection. The rationale for this assay is based on the property of SpA to bind most, if not all, VH3+ Ig's (22, 27). This property contrasts with the relative specificity of murine antibodies to human Ig's, which do not identify all VH3+ Ig's. For example, an mAb to VH3+ antibodies, called B6, recognizes the products of only approximately 10% of known human VH3 gene products (28). Since SpA has two binding sites on Ig's, it was necessary to first abrogate its Fc{gamma} binding site by iodination. We found that such a modified SpA (Tyr-SpA) binds only VH3+ Ig's. For example, whereas VH3+ mAb NG3B7 binds to biotinylated Tyr-SpA, human mAb's expressing members of other VH gene families do not ( Fig. 1). Using this specific and sensitive test, we were able to probe the proportion of VH3+ Ig's in serum samples. In HIV-1-seronegative individuals, we found that, in agreement with other reports (22, 29), VH3+ IgM, IgG, and IgA represented 32.5, 14.8, and 24.8% of total Ig's, respectively ( Table 3). HIV-infected subjects, however, showed important alterations. For the IgG isotype, VH3+ IgG concentrations were increased in infected subjects, but because the levels of IgG were high in both RPs and SPs ( Table 2), the proportion of VH3+ IgG antibodies was not significantly different from that of control subjects. VH3+ IgA's were dramatically diminished in RPs ( Table 3). With time, some RPs exhibited a progressive decrease of this subset, as compared to SPs ( Fig. 2).



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  		Figure 1. Detection of VH3+ human immunoglobulins. ELISA wells were coated overnight at 4°C with anti-human Ig antibodies. Ig dilutions were added and, after incubation with biotinylated, modified SpA (Tyr-SpA) binding was revealed with an alkaline phosphatase-labeled Extravidine conjugate. In this assay, Tyr-SpA binds human VH3+ mAb NG3B7 (ref 19), but not VH2+ mAb C31 (ref 19), VH4+ human mAb's T48.16-G8 (ref 19), F105D (ref 20), and VH5+ mAb 257-D (ref 21). NG3B7 monoclonal antibody (filled squares); F105D monoclonal antibody (open triangles); C31 monoclonal antibody (open circles); T48.16-G8 monoclonal antibody (open squares); 257-D monoclonal antibody (open diamonds).


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  		Table 3. Alterations of VH3+ Ig levels in HIV-infected subjects3tfa



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  		Figure 2. Quantification of VH3+ IgA throughout disease progression. A) Temporal evolution of VH3+ IgA (±SD) in SP subjects (stippled bars). The mean (±SD) of VH3+ IgA in HIV-1-seronegative subjects is shown (black bars). B) Progressive decline of VH3+ IgA (stippled bars) in RP patients. The mean (±SD) of VH3+ IgA in HIV-1-seronegative subjects is also shown (black bars).

To see whether these VH3+ antibody alterations are associated with reductions in the intensity of the HIV-specific antibody response, we probed the repertoire of antibodies specific for env gene products. We found that SPs have high titers of anti-gp160 antibodies compared with RPs ( Table 4). In addition, longitudinal studies in RPs and SPs showed that anti-gp160 antibody titers decrease with disease progression. VH3+ antibodies to gp160 followed a similar trend ( Fig. 3). Thus, disease progression is associated with a decrease of the magnitude of the humoral response and a progressive decline in HIV-specific VH3+ antibodies.


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  		Table 4. Reduced magnitude of the antibody response to gp160 in RPs4tfa



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  		Figure 3. Correlation between progressive decline of VH3+ anti-gp160 antibodies and HIV-1 viral load in a SP patient (SP-5). Quantitation of HIV-1 viral RNA was performed in the patient's serum samples by a nucleic acid sequence-based amplification method (23) using a kit from Organon Teknika (Boxtel, The Netherlands). Stippled bars: viral RNA; black bars: VH3+ anti-gp160 antibodies.

To understand the origin of these antibody alterations, we probed the antibody response to epitopes present on the C4, as well as the V4 domains and mapping to the gp120 SAg binding site (17, 18). The V3 neutralizing epitope was used as control. As predicted from the anti-gp160 antibody titers, the levels of anti-V3 antibodies were lower in the group of RPs compared with SPs. Antibodies to the C4 and V4 domains were present, albeit at lower titers, in both groups of seropositive subjects. Remarkably, although VH3+ antibodies to the V3 epitope were detectable, VH3+ antibodies to C4 and V4 peptides were completely absent in the serum of infected subjects from both groups ( Table 5, Fig. 4).


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  		Table 5. Absence of VH3+ antibodies targeted to the B-cell superantigen binding site of gp 1205tfa



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  		Figure 4. Depletion of VH3+ antibodies to epitopes that map to the gp120 superantigen binding site. A) Evolution of VH3+ antibodies to the V3 epitope (stippled bars) in a SP subject (SP-2). Remarkably, VH3+ antibodies to peptides within the gp120 superantigen binding site are absent (C4 epitope: black bars; V4 epitope: hatched bars). B) Progressive decline of VH3+ antibodies to the V3 epitope (stippled bars) in a RP patient (RP-1). VH3+ antibodies to peptides within the gp120 superantigen binding site are also absent (C4 epitope: black bars; V4 epitope: hatched bars).

It is unlikely that the absence of VH3+ antibodies to C4 and V4 epitopes is due to a limitation of the sensitivity of the method used. Previous studies of RP and SP patients showed that anti-gp120 antibodies represent 2–8% of total serum IgG (ref 30). Inasmuch as the RPs and SPs we have examined had approximately 19 mg/ml of total serum IgG, about 0.4 to 1.5 mg/ml of their IgG's are gp120 specific. Assuming that gp120 encompasses no more than 10 epitopes (31, 32), we estimate that the serum samples we tested contained 40 to 150 µg/ml of epitope-specific IgG antibodies and that, at 1/50 serum dilutions, 0.8 to 3 µg/ml of epitope-specific antibody were tested. Thus, with a sensitivity limit of 50 ng/ml, the ELISA test we used could not have missed the presence of C4- and V4-specific VH3+ antibodies.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
It is now recognized that, after viral infection, several strategies may be engaged by the immune system to mount a potent response and that an anti-HIV protective immunity can be mediated through a combination of cellular and humoral immunity, in the form of mucosal and neutralizing antibodies (7). Likewise, development of vaccines that simultaneously stimulate multiple components of the immune system would be desirable. To better define the correlates of protective immunity, we analyzed the humoral response of a group of HIV-1-infected subjects (SPs) with stable CD4+ counts who remained asymptomatic for more than 6 years. A second group of seropositive subjects (RPs) had a significant decrease of CD4+ counts and progressed to AIDS-related manifestations. We found that HIV-positive subjects are hypergammaglobulinemic and that RPs exhibit a marked hyperproduction of serum IgA. This result is consistent with previous reports showing that serum IgA is associated with disease progression and that it can even be used as a significant indicator of immunodeficiency (24, 25, 33). Not surprisingly, SPs had higher anti-gp160 and anti-V3 antibody titers than RPs. Thus, in line with previous findings (34), disease aggravation is associated with a decrease of the magnitude of the humoral response specific for env antigens.

To gain insight into the origin of these antibody abnormalities, we probed the antibody repertoire to HIV. Human VH genes have been classified into seven families, VH1 to VH7, with members of each family sharing >80% homology. With over 20 VH3 gene segments, the VH3 family makes the largest contribution (>50%) to the functional repertoire (15, 16) and imparts protection against infectious agents (27, 35). Here, however, we found dramatic alterations of VH3+ Ig's in RPs. Notable among these is the marked reduction of VH3+ IgA. Anti-HIV antibodies of the IgA isotype have been shown to possess neutralizing activity in vitro (36, 37). These alterations are reminiscent of previous reports showing that the VH3 gene family is underrepresented in several compartments of the immune system of HIV-1-seropositive individuals, including peripheral blood (11, 13), bone marrow (38), lymph node, and spleen (12, 39).

Analyzing the antibody response specific for HIV-1 env gene products, we found that VH3+ anti-gp160 antibody levels are low in RPs and show marked temporal fluctuations in SPs. These latter subjects are known to represent an heterogeneous group in terms of cytotoxic responses, viral strain phenotypes, and neutralizing antibody activities (40–42). Despite these variations, SPs displayed relatively stable levels of VH3+ antibodies to gp160 and to the V3 epitope with time. In contrast, RPs showed a progressive temporal decrease in VH3+ antibodies ( Fig. 4).

It is notable that the magnitudes of the changes seen among the various antibody subsets are different. First, the decline of total VH3+ antibodies is not as dramatic as the selective loss of VH3+ antibodies against gp120 in HIV-infected individuals. Thus, the depletion observed seems to be restricted to gp120 binding antibodies, suggesting that gp120 SAg is able to distinguish among B cells according to their antigen binding specificity. Second, it is remarkable that although there is a significant difference (a reduction of about 85%) in the total anti-gp160 antibodies between SP and RP sera, the anti-gp160 VH3+ antibody response of RPs accounts for a lower percentage of the total anti-gp160 antibodies (67%) compared to those expressed by SPs ( Table 4). This disparity between levels of total anti-gp160 antibodies and VH3+ anti-gp160 antibodies could indicate that non-VH3+ antibodies (approximately 20%) also suffer losses to account for the reductions in RP sera. However, we cannot exclude the possibility that higher avidity of VH3+ antibodies contributes disproportionately to the anti-gp120 response. In this regard, it is conceivable that somatic mutation accompanying SAg B cell stimulation could lead to the loss of the SpA binding site. If this were the case, the loss of VH3+ gp120 antibodies could be a marker for antibody maturation rather than loss of the B cell/antibody population. It will be important to probe levels of VH3 negative anti-gp120 antibodies with HIV infection and progression. Probing this antibody subset requires development of a test able to identify VH3 negative antibodies.

Several observations suggest that both the quality and quantity of anti-HIV-1 antibodies may influence disease progression. We propose that the paucity in VH3+ antibodies contributes to the ineffectiveness of the humoral immune response to HIV. Our findings that VH3+ IgA antibodies and VH3+ anti-gp160 antibodies both decrease further suggest that VH3+ antibodies play an important role in protection and that their underexpression may accelerate disease exacerbation. This view is supported by the observation that low levels of gp120 SAg binding are a significant factor in homosexual transmission of HIV-1 infection (43).

Our findings recall observations of an accelerated B cell apoptosis in the lymph nodes of HIV-infected subjects (44) and a progressive loss of peripheral B cells (11). Since it is unlikely that B cells are directly killed by the virus, indirect mechanisms must be involved. The gp120 SAg has been shown to react with human Ig's and B cells that express members of the VH3 gene family (14). Since this latter family dominates (>50%) the human antibody repertoire (15, 16) and because B cell SAg's bind the VH portion of Ig's and can trigger all B cells bearing the appropriate VH regardless of the other JH, DH, JL, and JH segments, the SAg property of gp120 has potential deleting consequences on the B cell repertoire of HIV-infected subjects (35). By analogy with the depleting activity of T cell SAg's in experimental animals (45), it is possible that the deletion of VH3+ B cells is triggered by a similar phenomenon. gp120 SAg binding to VH3+ B cells may render them anergic and prone to apoptosis. A further stimulus gives rise to an antibody repertoire deprived of a significant proportion (>50%) of its members. In support of this gp120 SAg-mediated pathway, we noted that VH3+ antibodies directed to the gp120 SAg binding site (17, 18) are absent in HIV-positive subjects and that the VH3+ antibody response to HIV antigens varies depending on the viral load ( Fig. 3).

Thus, paradoxically, despite continuous viral replication and persistent exposure of the immune system to gp120, there is a repertoire exhaustion and, hence, a humoral immunodeficiency. Consequently, there is a lack of continued diversification of the anti-HIV antibody response, and this B cell dysfunction contributes significantly to amplification of HIV-related immunodeficiency. Finally, it is currently thought that vaccines designed to elicit potent humoral immune responses to beneficial HIV domains while limiting the response to harmful domains, together with a potent cellular immunity, may prove beneficial in preventing infection. Our findings suggest that epitopes within the gp120 SAg binding site should be excluded from candidate vaccine preparations.


   ACKNOWLEDGMENTS
 
We are indebted to Dr. J.-J. Lefrère (INTS, Paris) for providing the HIV-positive serum samples, to Dr. M.-P. Kieny (Transgène, Strasbourg) for the generous gift of recombinant proteins, to Drs. D. Goossens (INTS, Paris) and C. Desgranges (INSERM, Lyon, France) for kindly providing monoclonal antibodies, and to M. Debbia for technical assistance. We thank the Agence Nationale de Recherche sur le SIDA (ANRS, Paris) and the AIDS National Institute of Allergy and Infectious Diseases, Research and Reference Reagent Program, Division of AIDS, National Institutes of Health from MicrogeneSys (West Haven, Conn.) for HIV synthetic peptides. This work was supported by grants from the Institut Pasteur and the Fondation pour la Recherche Médicale (FRM, SIDACTION). L.J. was a postdoctoral fellow of the FRM and M.Z. is an investigator of the Institut National de la Recherche et de la Santé Médicale (INSERM).


   FOOTNOTES
 
1 Correspondence: Département d'Immunologie, Institut Pasteur, 28 rue Dr Roux, 75015 Paris, France.

2 Abbreviations: HIV, human immunodeficiency virus; Ig, immunoglobulin; mAb, monoclonal antibody; RP, rapid progressor; SAg, superantigen; SP, slow progressor; SpA, Staphylococcus aureus protein A; Tyr-SpA, tyrosine-modified SpA; ELISA, enzyme-linked immunoassay.

Received for publication March 11, 1998. Revision received May 10, 1998.
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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